Derivatives of the benzotetronic acid and processes for manufacturing same



Sept. 20, 1949; J. ROSICKY 7 ,4 0

DERIVATIVES OF THE BENZOTETRONIC ACID AND PROCESSES FOR MANUFACTURING SAME Filed Feb. 14, 1 47 Prothrombin I I I l I I I l v 0 2 4 6 8 I012 I4 [6 I8 20 2 2 2 4 2 6 28 3 0 32 Hours Inventor I J on R 05 I C K Y B, Mx-\ amm AH or n e y Fatentecl Sept. 2Q, 1949 p UNITED STATES am OFFICE DERIVATIVES OF THE BENZOTETRONIC ACID AND PROCESSES FOR MANU- FACTURING SAME Jan Rosicky, Prague, Czechoslovakia, assignor to Spojene farmaceuticke zavody, narodni podnik, Prague, Czechoslovakia Application February 14, 1947, Serial No. 728,714

In Germany March 18, 1944 Section 1, Public Law 690, August 8, 1946 Patent expires March 18, 1964 Y 4 Claims. (Cl. 260344.6)

, 1 r W 2. v c

The invention is concerned with the manufac- The reaction between two molecules of benzoture of derivatives of the benzotetronic acid and Itetronic acid and .one'molecule of glyoxylic acid more particularly of derivatives which are valethyl ester is as follows: uable for the control of the prothrombin level of C 0002B I the blood. 5 OH 4 OH It is known that 3,3'-methylenebis-(4-hydroxyt t coumarin) when administered internally will greatly reduce the coagulability of the blood and I l J l :5 extend the time of coagulation. Q

Animal tests have proved that the duration of 10 o 0 the effect of this compound is very prolonged. OH OH Thus, for instance, after a single dose of 5 milli- I I grams per kilogram administered to a rabbit, the minimum level of the prothrombin drop will be reached within approximately two days, is held 6 for two to three days and only on the sixth to o seventh day the return to normal will start, as shown on Fig. 1 of the accompanying drawings This condensation product may be considered which will be described more in detail hereinafter. as 3,3 carboxymethylenebis-(4-hydroxycouma- This slow return to normal of the prothrombin rin) ethyl ester.

level is, in many cases, of great disadvantage for n interesting DheHOmenon Was O ve When a clinical application of this known method, h m ltin point was e n Th pro t since, even if desired, an interruption of this conas first obtained melts at 1'72 to 174 C. When dition is impossible. Even the administration of h p c s recrystallized from dil e acet c high doses of vitamin K cannot cause the return acid, this melting po remains unchanged; if

to normal of the prothr mbin1eve1 crystallized from methyl alcohol, the melting A primary object of this invention therefore po t de eases to 153 to 154 C. is the manufacture of a preparation the effect s pr d t f wer l i po n may be of which Starts more rapidly and decreases more reconverted by recrystallization into the product rapidly, thus makes possible to interrupt, if deof hlghel' meltmg Point sired, the eifect on the prothrombin level or to Theproduct acts as Weak acld and is Soluble extend thiS efie t by a renewed administration in a bicarbonate solutlon and in alkalis, whereof the dose from it may be re-precipitated by means of hy- A novel compound highly effective for the condrochlolilc acld' trol of the prothrombin level is obtained when, In ammal tests the product of the mventlon in accordance with my invention, benzotetronic reacts as follows: i

When the product is administered per os to a acid or 4-h dro coumar d y Xy m is con ensed Wlth rabbit in a dose of 5 m1ll1grams per kilogram of glyoxyu? acid ethyl ester The condensation may weight of the rabbit the decrease of the blood j sjgz is t i i f 40 prothrombin starts already within a short while p o a 8 m er a 0 mg and reaches the lowest level in the average within temperature t 18 hours, the titre movin betwee 20 t 30 The reaction product, for instance of the reacthe normal Value, determighed by g f gi g tion between benzotetronic acid and glyoxylic In the drawings annexed hereto, I heWe Shown acid ethyl ester, will remain unchanged when 4 this result in com n heated with alcoholic potassium. When heated tion of t same f 1 33; 22: g ai iggggi to 230 0., carbon dioxide will escape and the 4-oxycoumarin.

residue will melt not below 300 C'., which is con- In the drawings:

clusive of the fact that condensation had taken Fig. 1 shows the course of the prothrombin place, level in per cent of the normal value with time when methylene-bis-4-oxycoumarin is administered to a rabbit; whereas Fig. 2 shows the corresponding course of the prothrombin level onadministration of the product of the invention.

Whereas in the case of Fig. 1, the normal prothrombin level will be reached only after 9 days, the normal level in the case of Fig. 2 is already restored after approximately 30 hours.

Histological tests of organs did not show any changes, solely an accumulation of glycogen in the tissue of the liver. Particularly, after administration during an extended period of time, no

damage to the capillaries was observed, in contrast with the administration of methylene-bis- 4-oxycoumarin where such damages have been observed.

The following example Will illustrate the manufacture of the compounds of the invention. It will be readily understood however that this example is illustrative of the invention but not limitative of its scope.

Example '7 gm. of benzotetronic acid are dissolved in 750 cc. of waterat boiling temperature and thereafter '7 gm. of glyoxylic' acid ethyl ester are added. After a short while the liquid becomes turbid and gradually a white deposit is separated. The deposit is filtrated and dried in vacuo. The melting point is 1'72 to 174 C.; after recrystallization from methyl alcohol 153 to 154 C.

The crude product is dissolved in sodium lye, filtrated by means of animal charcoal, precipitated by means of hydrochloric acid, and re-' it by means of,anacid, and recrystallizing it.

4. As a new compound: 3,3-carboxymethy1- enebisl-hydroxycoumarin) ethyl ester and having the structural formula:

JAN ROSICKS'Z.

REFERENCES CITED The following references are of record in the file of this patent:

Sullivan et al.,-Journal of the Amer. Chem. Society, vol. 65, Dec.-194=3, pp. 2288-2291. 

